The objective of the proposed studies is to define the biological significance of specific MMPs and their natural inhibitors, the TIMPs, in the progression of or protection against ulcerative corneal disease. This will be done using infectious and sterile corneal ulcerative models induced by PA and alkali-burn, respectively. Comparative usage of these models will determine if similar MMPs or TIMPs are involved in each ulcerative process in which many aspects of disease pathology are remarkably similar. After identification of the involved MMPs and/or TIMPs, rational therapies could be implemented to provide specific targeting of the mediators involved in the elicitation of tissue destruction without compromising other MMPs/TIMPs that may prove integral to corneal remodeling and repair. For these studies, two hypotheses will be tested: Hypothesis 1: Following PA corneal challenge, abnormal regulation or excessive expression of specific MMPs results in progressive, irreversible tissue destruction, whereas expression of appropriate levels of one or more of the TIMPs leads to normal corneal tissue remodeling. Aims l and 2 are proposed to directly test this hypothesis. Aim 1: To elucidate and characterize specific MMPs (MMP-8, -9 and -13) in the pathogenesis of PA corneal infection using a young adult (resistant) vs aged (susceptible) inbred mouse model. Aim 2: To similarly examine specific TIMPs (TIMP-1 and -4) in the pathogenesis of PA corneal infection using a resistant vs susceptible inbred mouse model. Hypothesis 2: The ability to restore corneal clarity/ocular integrity following moderate vs severe alkali-burns is dependent upon the hosts' ability to appropriately regulate the expression of individual MMPs and their inhibitors in a manner which promotes overall corneal tissue remodeling. Aims 3 and 4 are proposed to directly test this hypothesis. Aim 3: To elucidate and characterize specific MMPs (MMP-8, -9 and -13) in the pathogenesis of corneal alkaliburn in inbred mice using moderate (restore corneal clarity) vs severe (cornea perforates) burns. Aim 4: To similarly examine specific TIMPs (TIMP-1 and -4) in the pathogenesis of corneal alkali-burn in inbred mice using moderate vs severe burns.